EP2114252B1 - Cartographie cardiaque indépendante des phases - Google Patents

Cartographie cardiaque indépendante des phases Download PDF

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Publication number
EP2114252B1
EP2114252B1 EP08719459.3A EP08719459A EP2114252B1 EP 2114252 B1 EP2114252 B1 EP 2114252B1 EP 08719459 A EP08719459 A EP 08719459A EP 2114252 B1 EP2114252 B1 EP 2114252B1
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Prior art keywords
map
vessel
image
angiogram
life
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German (de)
English (en)
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EP2114252A2 (fr
Inventor
Raoul Florent
Stephane Valente
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Koninklijke Philips NV
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Koninklijke Philips NV
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/50—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications
    • A61B6/504—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications for diagnosis of blood vessels, e.g. by angiography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/12—Arrangements for detecting or locating foreign bodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/48—Diagnostic techniques
    • A61B6/481—Diagnostic techniques involving the use of contrast agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/52—Devices using data or image processing specially adapted for radiation diagnosis
    • A61B6/5211—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data
    • A61B6/5229—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data combining image data of a patient, e.g. combining a functional image with an anatomical image
    • A61B6/5235—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data combining image data of a patient, e.g. combining a functional image with an anatomical image combining images from the same or different ionising radiation imaging techniques, e.g. PET and CT
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/44—Constructional features of apparatus for radiation diagnosis
    • A61B6/4429—Constructional features of apparatus for radiation diagnosis related to the mounting of source units and detector units
    • A61B6/4464—Constructional features of apparatus for radiation diagnosis related to the mounting of source units and detector units the source unit or the detector unit being mounted to ceiling

Definitions

  • the invention relates to the field of interventional imaging.
  • the invention relates to an examination apparatus for cardiac roadmapping for examination of an object of interest, to a method for cardiac roadmapping, a computer-readable medium, a program element and an image processing device.
  • an imaging system for PTCA Percutanerous Transluminal Coronary Angioplasty
  • PTCA Percutanerous Transluminal Coronary Angioplasty
  • a navigation system may therefore help the cardiologists by providing a cardiac roadmap displayed next or overlaid on the live fluoroscopy pictures.
  • this cardiac roadmap represents the vessel network acquired during angiography, with the same cardiac phase than the current live image.
  • Documents [1] and [2] describe a basic method for realising cardiac roadmapping. They rely on the extraction of the cardiac and respiratory cycles, and on the matching of those cycles between the angiogram images (in filled state) and the live images.
  • [3] a refinement of [1], [2] is proposed that consists in registering the guidewire tip with the roadmapping data.
  • a vessel map is computed from the angiogram image that corresponds to the considered live image (this correspondence being established for instance following the cycle-centric approach of [1], [2]), and the guidewire tip is extracted from the live image. The extracted tip is then brought into registration with the vessel map. This may help to improve the correct matching between the roadmap and the intervention device.
  • WO 2006/103644 A1 describes automatic detecting and tracking of a device, such as a guide wire tip, catheter tip or intravascular therapeutic device, within a tubular organ, such as an artery or a blood vessel.
  • the detecting and tracking uses fluoroscopic images taken prior to or during a catheterization operation.
  • the devices are fused with images or projections of models depicting the tubular organs using a constrained correlation, applying a requirement for markers detected in the fluoroscopic image tob e translated to a vessel in a reference image or a last injection image.
  • the invention provides a computer-implemented method for cardiac roadmapping, an examination apparatus, a computer-readable medium, and a computer program product, according to the independent claims.
  • a computer-implemented method for cardiac roadmapping for examination of a vessel tree is provided in accordance with claim 1.
  • a registration of whole image sequences may be performed globally without having to perform an image selection or pairing in a first step followed by an image registration in a second step.
  • a cardiac roadmapping technique that does not rely on the prerequisite of a phase-centric pairing of the angiogram and life images. Instead, both the pairing and accurate registration of the angiogram and life images are combined within a single operation.
  • This operation may comprise a global registering of a device-map sequence, incrementally built at life-time, with a vessel-map sequence built during angiogram creation.
  • This global motion-compensated association process may rely on map similarities, but may also enforce temporal coherency.
  • the cardiac roadmapping is based on object enhancement, in which case two or more objects are identified in the life-image and in the angiogram image in order to provide for an image registration, i.e. correlation determination. No phase measuring is necessary.
  • At least one of the objects is identified using an object-specific technique.
  • a catheter injection tip at a pivotal point of the vessel tree is identified, for which the object-specific technique involves looking at the injection tip at a location near a border of the live image.
  • a registration of the vessel-map and the device-map derived on the basis of this identification may be provided without involving an extra pairing or phase measuring step.
  • the second image is binary or multi-valued, reflecting a likelihood of the presence of the first object and the second object.
  • the second object is a guidewire or a balloon marker or a stand marker inserted into a coronary of the vessel-tree.
  • the examination apparatus is adapted for issuing an alarm if no detection of the first object or the second object is performed.
  • an alarm signal is generated to warn the user.
  • the first image sequence is a vessel-map sequence and the second image sequence is a device-map sequence.
  • the device-map sequence is a life-time sequence acquired during an intervention of the object of interest.
  • the global correlation determination comprises a definition of a class of geometrical transforms.
  • Such a class of geometrical transforms may, for example, be the class of all the translations belonging to a certain range. Furthermore, the class may comprise other rigid transforms, such as rotation or shearing, or even non-rigid transforms.
  • the global correlation determination comprises a comparison of device-maps of the device-map sequence to vessel-maps of the vessel-map sequence, resulting in a similarity S[D i ,V j ,T k ] between each device-map of the device-map sequence and each vessel-map of the vessel-map sequence.
  • all the geometrically transformed causal device-maps may be compared via a given similarity criterion to all the vessel-maps of the useful angiogram part.
  • the global correlation determination comprises an optimization of a measure function K[A], which relates to the similarity.
  • the optimization of the measure function enforces a temporal coherency H[A].
  • the device-map sequence may be a causal device-map sequence.
  • the vessel-map sequence is generated from one of an angiogram data set and an isolated sub-set of the angiogram data set, wherein the vessel-map sequence comprises a plurality of vessel-map images.
  • the vessel-map image of the vessel-map sequence is generated on the basis of a vessel-enhanced image.
  • each vessel-map image of the vessel-map sequence is computed on the basis of a full isolated sub-set of the angiogram data set.
  • an isolation of a sub-set of the angiogram data set is performed on the basis of at least one of a histogram-based procedure and a threshold-based procedure.
  • the device-map sequence is generated from a life-image data set.
  • the device-map sequence may be generated on the basis of at least one of a position of a guidewire or a marker.
  • the examination apparatus is configured as one of the group consisting of a material testing apparatus, a medical application apparatus and a micro CT system.
  • a field of application of the invention may be medical imaging or baggage inspection.
  • the examination apparatus is adapted as one of a three-dimensional computed tomography apparatus and a three-dimensional rotational x-ray apparatus.
  • a method for cardiac roadmapping for examination of an object of interest with an examination apparatus in which a cardiac roadmapping is performed on the basis of at least one of a global correlation determination of a first image sequence of the object of interest and a second image sequence of the object of interest and a correlation determination of a first image of the object of interest and the second image of the object of interest on the basis of an identification of a first object and a second object in the first image and the second image.
  • an image processing device for cardiac roadmapping for examination of an object of interest comprising a memory for storing a data set of the object of interest and which is adapted for carrying out the above-mentioned method steps.
  • a computer-readable medium in which a computer program for cardiac roadmapping is stored which, when being executed by a processor, causes the processor to carry out the above-mentioned method steps.
  • a program element for cardiac roadmapping for examination of an object of interest when being executed by a processor, causes the processor to carry out the above-mentioned method steps.
  • the method of examination of the object of interest may be embodied as the computer program, i.e. by software, or may be embodied using one or more special electronic optimization circuits, i.e. in hardware, or the method may be embodied in hybrid form, i.e. by means of software components and hardware components.
  • the program element may preferably be loaded into working memories of a data processor.
  • the data processor may thus be equipped to carry out exemplary embodiments of the methods of the present invention.
  • the computer program may be written in any suitable programming language, such as, for example, C++ and may be stored on a computer-readable medium, such as a CD-ROM.
  • the computer program may be available from a network, such as the WorldWideWeb, from which it may be downloaded into image processing units or processors, or any suitable computers.
  • a registration of images relating to an angiogram data set and images relating to a life-time data set is performed without an additional pairing or image selection step. No identification of a cardiac or respiration phase has to be performed. Therefore, an electrocardiogram or lung monitoring equipment is not necessary.
  • Fig. 1 shows a schematic representation of an exemplary rotational X-ray scanner in which a method according to the invention may be implemented.
  • An X-ray source 100 and a flat detector 101 with a large sensitive area are mounted to the ends of a C-arm 102.
  • the C-arm 102 is held by curved rail, the "sleeve" 103.
  • the C-arm can slide in the sleeve 103, thereby performing a "roll movement" about the axis of the C-arm.
  • the sleeve 103 is attached to an L-arm 104 via a rotational joint and can perform a "propeller movement" about the axis of this joint.
  • the L-arm 104 is attached to the ceiling via another rotational joint and can perform a rotation about the axis of this joint.
  • the various rotational movements are effected by servo motors.
  • the axes of the three rotational movements and the cone-beam axis always meet in a single fixed point, the "isocenter" 105 of the rotational X-ray scanner.
  • the shape and size of this "volume of projection" (VOP) depend on the shape and size of the detector and on the source trajectory.
  • the ball 110 indicates the biggest isocentric ball that fits into the VOP.
  • the object e.g.
  • a patient or an item of baggage) to be imaged is placed on the table 111 such that the object's VOI fills the VOP. If the object is small enough, it will fit completely into the VOP; otherwise, not. The VOP therefore limits the size of the VOI.
  • Each triple of C-arm angle, sleeve angle, and L-arm angle defines a position of the X-ray source. By varying these angles with time, the source can be made to move along a prescribed source trajectory.
  • the detector at the other end of the C-arm makes a corresponding movement.
  • Fig. 2 shows a schematic representation of an image 201 of an angiography-sequence and an image 202 of a life-sequence for registration according to an exemplary embodiment of the present invention.
  • the image 201 shows the vessel-tree 203 and the image 202, which is acquired during an intervention, shows a guidewire 204 inserted into the vessel-tree 203.
  • the targeted device has a very limited breadth as compared to the breadth of vessels in the filled angiogram. As a matter of fact, this also applies to other possible intervention devices such as the balloon markers (mentioned once in [3]), or the catheter injection tip from where the contrast agent flows into the coronaries (the catheter is not mentioned in [3] as a possible targeted device).
  • the discrepancy between the breadth of the vessels in the angiogram image and the breadth of the segmented object in the corresponding live image may be bound to lead to high registration inaccuracies. For instance, if the tip is rather straight (which is very often the case), it can reasonably fit into any straight vessel section that shows the same orientation (assuming a simple translation-based registration process). This of course may end up to a highly undiscriminating situation, prone to considerable registration mistakes.
  • the present invention may improve this situation and may suppress the high degree of inaccuracy of the method described in [3].
  • intervention objects are simultaneously present and detected (or enhanced). This may improve the registration of the roadmap and of the live image during cardiac roadmapping.
  • the invention proposes to enforce the presence of catheter injection tip in both the angiogram and the live image and to combine the injection tip detection with the detection of another intervention device such as the guidewire tip and/or balloon/stent markers.
  • the privileged location of the injection tip at a pivotal point of the vessel network anatomy, combined with a more distal device location such as the guidewire tip's location is an essential element for the robustness of the angiogram vessel map and of a multi-device map.
  • the injection tip is not necessarily present in both the angiogram and the live image.
  • the intervention protocol is slightly modified to enforce this presence in both the angiogram and the live image, together with the presence of a second intervention device in the live image. This may improve the vessel-to-device registration operation.
  • the detection and registration methods proposed by this invention differ from [3] in that the well-identified nature of the involved objects may allow for higher specificity at the detection phase, and lower complexity at the registration phase (see below).
  • the invention both proposes an interventional protocol constraint and a detection / registration method for cardiac roadmapping.
  • An aspect of the invention stipulates that two distinct devices should be present in the live image, and their corresponding anatomical locations should be visible in the angiogram image.
  • the invention stipulates that:
  • Fig. 3 shows a flow-chart of an exemplary embodiment of a detection/registration method according to the present invention.
  • Step 1 Vessel map creation
  • the method relies on the construction of a vessel map, which may simply be a vessel segmentation image or a map that provides, for each pixel, the likelihood of vessel presence.
  • a vessel map which may simply be a vessel segmentation image or a map that provides, for each pixel, the likelihood of vessel presence.
  • the catheter injection tip should be part of this vessel map.
  • Step 2 Multi-device map creation
  • the second step is applied to the live image. It consists in building a device map that accounts for the presence of a least two distinct intervention devices. Those devices are very specific and the map creation method can take advantage of this specificity. For each device nature, a specialised technique might be involved. For instance, one might take into account the device scale, expected breadth and location. In particular, the injection tip is to be looked for near the image borders or shutter borders. When object-specific techniques are used, several device maps might be separately created and then eventually merged into a single multi-device map accounting for all the targeted devices.
  • the composite device map might be binary, or as in the vessel case, multi-valued, reflecting the likelihood of the presence of each targeted device.
  • Step 3 Vessel map to device map registration
  • the registration process may then be applied. It comprises the step of finding the geometrical transformation (among a pre-defined class of possible transformations) that maximizes the similarity between the vessels and the multi-device roadmaps. Several similarity measurements may be considered.
  • the first step consists of pairing the current live image with a given angiogram image thanks to the matching of their cardiac phases (plus possibly the matching of their respiratory phases).
  • this pairing may rely on the ECG signal or on image-based cardiac phase determination (this is often referred to as the kymogram method).
  • any method that strongly relies on the cardiac / respiratory phase correlation between the angiogram and the live parts of the intervention may naturally be exposed to all sort of robustness problems.
  • a cardiac roadmapping technique that does not rely on the prerequisite of a phase-centric pairing of the angiogram and live images. Instead, both the pairing and accurate registration of the angiogram and live images are combined within a single operation.
  • This operation comprises a global registering of a (causal) device-map sequence, incrementally built at live time, with a vessel-map sequence built during angiogram creation.
  • This global motion-compensated association process relies on map similarities, but may also enforce temporal coherency.
  • the invention may produce a cardiac roadmap without the help of any ECG signal or its image-based surrogate (kymogram).
  • the invention may lead to a more robust cardiac roadmapping, capable of coping with arrythmic disorders, cardiac rhythm instabilities, and respiratory cycle or depth changes.
  • Fig. 4 shows a flow-chart of another exemplary embodiment of a method according to the present invention.
  • Step 1 Determination of the useful part of the angiogram
  • the first step consists of isolating from the total angiogram sequence a subset of consecutive images that contains a sufficient amount of contrast agent, thus featuring a good contrast of the vessels set against the background.
  • Simple histogram-based or thresholding techniques applied to the vessel-enhanced angiogram images may be used to compute this subset isolation.
  • Step 2 Creation of a vessel-map sequence from the useful angiogram part
  • a vessel-map image refers to an image where the pixel values are representative of the likelihood of vessel presence at that pixel.
  • the values can either be binary (designating presence or absence certainty), or they can vary within a certain range, thus measuring a degree of presence likelihood.
  • a vessel-map image can be built from a vessel-enhanced image, using for instance the approach described in [4]. But many other techniques are also possible.
  • a vessel-map sequence may simply be constituted of vessel-map images, as described above.
  • the full input sequence (the useful angiogram part) is used to compute each elementary vessel-map image of the sequence. This is typically the case when motion information is used to discriminate between vessel and non-vessel structures.
  • the vessel-presence likelihood may be replaced or augmented with a vessel-proximity likelihood, for instance using a distance transform.
  • Step 3 Creation of a causal live device-map sequence up until the current time
  • a causal device-map sequence is built.
  • the considered devices may for instance be, but not exclusively, the guidewire tip or balloon/stent markers.
  • the term “causal” simply refers to the fact that the device-map sequence is built up to the current time and no further.
  • the device-map sequence up to time t can be built from the device-map computed up to t-1, augmented with a device-map at time t. However, this is not necessarily the case.
  • Step 4 Global correlation of the causal device-map and vessel-map sequences
  • This final part may be the most important step according to this exemplary embodiment of the present invention.
  • all the geometrically transformed causal device-maps can be compared via a given similarity criterion to all the vessel-maps of the useful angiogram part (now simply referred to as the angiogram).
  • Index t designates the current time.
  • Term H[A] enforces the temporal coherency of the association A over the full interval [0, t]. This terms aims at capturing the continuous nature of the image acquisition process and of the involved respiratory and cardiac motions.
  • ⁇ and ⁇ are simple normalisation constants, and the negative sign in front of ⁇ simply accounts for the fact that one looks for high map similarity values, but low inter-transform distance values.
  • Fig. 5 shows an exemplary embodiment of a data processing device 500 according to the present invention for executing an exemplary embodiment of a method in accordance with the present invention.
  • the data processing device 500 depicted in Fig. 5 comprises a central processing unit (CPU) or image processor 501 connected to a memory 502 for storing an image depicting an object of interest, such as the heart of a patient or an item of baggage.
  • the central processing unit 502 may comprise a determination unit (not depicted in Fig. 5 ) according to an aspect of the present invention.
  • the data processor 501 may be connected to a plurality of input/output network or diagnosis devices, such as a computer tomography scanner.
  • the data processor 501 may furthermore be connected to a display device 503, for example, a computer monitor, for displaying information or an image computed or adapted in the data processor 501.
  • An operator or user may interact with the data processor 501 via a keyboard 504 and/or other input or output devices, which are not depicted in Fig. 5 .
  • the bus system 505 it may also be possible to connect the image processing and control processor 501 to, for example, a motion monitor, which monitors a motion of the object of interest.
  • a motion monitor which monitors a motion of the object of interest.
  • the motion sensor may be an exhalation sensor.
  • the motion sensor may be an electrocardiogram.
  • ECG or exhalation data are, according to an aspect of the invention, not necessary.
  • Cardiac roadmapping according to the invention is perceived as a possible breakthrough since it may offer to the cardiologist an unprecedented way of achieving PTCA interventions with less contrast agent, less dose, less time, and more security.
  • the global correlation determination comprises an optimisation of a measure function K[A], which relates to the similarity.
  • the optimisation of the measure function enforces a temporal coherency H[A].
  • the device-map sequence is a causal device-map sequence.
  • the vessel-map sequence is generated from one of an angiogram data set and an isolated sub-set of the angiogram data set, wherein the vessel-map sequence comprises a plurality of vessel-map images.
  • a vessel-map image of the vessel-map sequence is generated on the basis of a vessel-enhanced image.
  • each vessel-map image of the vessel-map sequence is computed on the basis of a full isolated sub-set of the angiogram data set.
  • an isolation of a sub-set of the angiogram data set is performed on the basis of at least one of a histogram-based and a threshold-based procedure.
  • the device-map sequence is generated from a life-image data set.
  • the device-map sequence is generated on the basis of at least one of a position of a guidewire or a marker.
  • the object of interest is a vessel-tree.

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Claims (10)

  1. Procédé mis en oeuvre par ordinateur pour une cartographie cardiaque destinée à un examen d'une arborescence vasculaire, comprenant :
    - la dérivation d'une carte vasculaire à partir d'une angiographie de l'arborescence vasculaire ;
    - l'identification d'au moins deux objets d'intervention distincts dans une image en direct de l'arborescence vasculaire en utilisant des techniques spécifiques à l'objet pour au moins l'un des objets, dans lequel un premier objet d'intervention est un embout d'injection de cathéter à un point charnière de l'arborescence vasculaire, pour lequel la technique spécifique à l'objet implique la recherche de l'embout d'injection à un emplacement proche d'une frontière de l'image en direct ;
    - la dérivation d'une carte de dispositif vital sur la base de l'identification ; et
    - la corrélation de la carte vasculaire et de la carte de dispositif vital.
  2. Procédé selon la revendication 1,
    dans lequel la carte de dispositif vital est binaire ou à valeurs multiples, en reflétant une probabilité de la présence du premier objet et du deuxième objet.
  3. Procédé selon la revendication 1,
    dans lequel le deuxième objet d'intervention est un fil de guidage ou un marqueur de ballonnet ou un marqueur d'endoprothèse inséré dans une artère coronaire de l'arborescence vasculaire.
  4. Procédé selon la revendication 1,
    comprenant en outre le déclenchement d'une alarme si aucune détection du premier objet ou du deuxième objet n'est effectuée.
  5. Procédé selon la revendication 1, dans lequel l'identification des au moins deux objets comprend l'utilisation de techniques spécifiques à l'objet pour chaque objet.
  6. Procédé selon la revendication 5, dans lequel la dérivation de la carte de dispositif vital comprend la création de cartes de dispositif distinctes pour chaque objet sur la base des techniques d'identification spécifiques à l'objet, et la fusion des cartes de dispositif distinctes en une seule carte de dispositifs multiples en tant que la carte de dispositif vital.
  7. Appareil d'examen pour un examen d'une arborescence vasculaire, comprenant une unité de détermination configurée pour effectuer les étapes d'un procédé selon l'une quelconque des revendications 1 à 6.
  8. Appareil selon la revendication 7, configuré en tant qu'un scanner rotatif à rayons X.
  9. Produit de programme informatique pour une cartographie cardiaque, comprenant un ensemble d'instructions qui, lorsqu'elles sont exécutées par un processeur (401), amènent le processeur à effectuer les étapes d'un procédé selon l'une quelconque des revendications 1 à 6.
  10. Support lisible par ordinateur sur lequel est mémorisé le produit de programme informatique selon la revendication 9.
EP08719459.3A 2007-02-28 2008-02-25 Cartographie cardiaque indépendante des phases Active EP2114252B1 (fr)

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EP08719459.3A EP2114252B1 (fr) 2007-02-28 2008-02-25 Cartographie cardiaque indépendante des phases

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EP07103243 2007-02-28
EP08719459.3A EP2114252B1 (fr) 2007-02-28 2008-02-25 Cartographie cardiaque indépendante des phases
PCT/IB2008/050668 WO2008104921A2 (fr) 2007-02-28 2008-02-25 Cartographie cardiaque indépendante des phases

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EP2114252A2 EP2114252A2 (fr) 2009-11-11
EP2114252B1 true EP2114252B1 (fr) 2018-04-11

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WO (1) WO2008104921A2 (fr)

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CN101621965A (zh) 2010-01-06
CN101621965B (zh) 2015-08-26
US8554308B2 (en) 2013-10-08
US20100145193A1 (en) 2010-06-10
WO2008104921A2 (fr) 2008-09-04
WO2008104921A3 (fr) 2008-11-06

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